Background Currently, heparin is used routinely for anticoagulation during cerebral angiography and neurointerventional procedures. In patients with heparin sensitivity, however, heparin cannot be used. Therefore, an alternative method of anticoagulation is necessary to prevent clot formation during such procedures.
Methods Argatroban, a direct thrombin inhibitor, is used as an alternate to heparin for anticoagulation. It is indicated for treatment of heparin induced thrombocytopenia as well as for prophylaxis during percutaneous coronary intervention. There are no reports describing the protocols for its use during neurointerventional procedures. We report on a series of three patients where argatroban was used in a series of three patients who underwent endovascular interventional procedures.
Results Argatroban was given in a loading dosage of 4 μg/kg/min for 10 min followed by an infusion of 1.0 μg/kg/min. During the procedure, no procedural complications were reported. Activated thrombin time was used to monitor anticoagulation.
Conclusions We describe here the use of argatroban as an alternate anticoagulant during such procedures, as well as outline our protocol for its administration.
Statistics from Altmetric.com
During cerebral angiography, the use of heparin reduces the risk of both peri- and postprocedural thromboembolism.1 However, heparin is contraindicated in those patients with heparin induced thrombocytopenia (HIT).2 Therefore, other means of anticoagulation are necessary to prevent procedural complications. The risk of HIT in patients treated with subarachnoid hemorrhage have been reported to be up to 6% in a large sample size.3 Alternative methods to heparin anticoagulation include the use of direct thrombin inhibitors (DTIs) or factor Xa inhibitors. However, none of the available factor Xa inhibitors are indicated for the treatment of HIT, making DITs the only alternate drugs of choice for HIT treatment. The formulary at our institution provides argatroban and bivalirudin (both DTIs) as alternative treatments for HIT. Unlike argatroban, which is metabolized in the liver, bivalirudin is cleared via the kidney. Since the metabolic load on the kidney is already high in these procedures due to the contrast agents used, we have opted to use argatroban rather than bivalirudin to avoid any further renal burden. We report here on the use of argatroban during cerebral angiography as an alternative to heparin.
Argatroban (GlaxoSmithKline, Research Triangle Park, North Carolina, USA) is a direct thrombin inhibitor derived from L-arginine. It reversibly binds the active site of thrombin and, unlike heparin, it does not require antithrombin III as a cofactor. Argatroban functions by inhibiting clotting cascade reactions that are catalyzed by thrombin. These reactions include the activation of clotting factors V, VIII, XIII, and protein C, as well as fibrin polymerization, and platelet aggregation. Argatroban has little effect on other serine proteases, such as factor Xa, plasmin, or kallikrein.
Because argatroban can inhibit both free and clot associated thrombin, it can be used both as thrombus prophylaxis and also in patients with an existing thrombus. It is hepatically metabolized and therefore it is safe for use in patients with renal impairment. Furthermore, argatroban does not interact with heparin induced antibodies, nor does it induce antibody formation,4 ,5 making it a safe alternative for use in patients with established heparin sensitivity.
Today, argatroban is approved by the Food and Drug Administration for anticoagulation in patients with HIT and for prophylaxis during percutaneous coronary intervention (PCI). Off-label indications include, but are not limited to, cardiac surgical procedures, cerebral thrombosis, disseminated intravascular coagulation, and prophylaxis in hemodialysis patients. Its use by neurointerventionalists for cerebral angiography, however, has not previously been documented. Nevertheless, there are reports of successful use of argatroban during carotid endarterectomy6–8 for symptomatic carotid stenosis.
Side effects and contraindications
The most significant adverse reactions reported with argatroban use are major and minor hemorrhage. Major hemorrhage is defined as overt bleeding with a corresponding decrease in hemoglobin by ≥2 g/dL requiring transfusion of ≥2 units. Minor hemorrhage is characterized by overt bleeding not meeting the criteria for a major hemorrhage.4 ,9 Overall risk for major hemorrhage is 5.3%, with gastrointestinal bleeding constituting the majority of cases at 2.3%.4 ,9 Additionally, all studies examining the use of argatroban during PCI have not reported any intrancranial hemorrhage4 ,9 ,10 with argatroban monotherapy. However, in patients receiving concomitant thromobolysis, intracranial bleeding was reported in 1% of patients.10 Furthermore, while intracranial bleeding has not been reported in patients receiving argatroban monotherapy during PCI, it has been reported with the use of another DTI, bivalirudin, in 0.03% of patients.11 There have been no reports investigating argatroban monotherapy during neurointerventional procedures and only a few reports examining the use of argatroban combination therapy during neurointerventional procedures. In these studies looking at argatroban combination therapy, intracranial hemorrhage occurred in 6.2% of patients.12 ,13 Patients with minor hemorrhage had either gastrointestinal bleeding (14.4%) or genitourinary bleeding/hematuria (11.6%).4 ,9 Other non-hemorrhagic events include dyspnea (8.1%), hypotension (7.2%), fever (6.9%), diarrhea (6.2%), sepsis (6.0%), and cardiac arrest (5.8%).4 ,9
Argatroban is contraindicated in patients who have existing bleeding or in those patients who are allergic to argatroban or its components. Furthermore, caution should be used when using argatroban if there is an increased risk for hemorrhage, for example in those patients who have congenital or acquired bleeding disorders.
Administration and monitoring
Argatroban is available only as an intravenous formulation, and dosing changes depending on if it is used for HIT treatment or prophylactically in PCI. Additionally, when used during angiography procedures, any oral anticoagulation the patient is on must be stopped before argatroban can be administered. For treatment of HIT, a dose of 0.5–2.0 μg/kg/min infusion is used.14 ,15 For PCI, loading doses are reported as ranging from 250 to 350 μg/kg given as an intravenous bolus followed by maintenance doses of 15–25 μg/kg/min via intravenous infusion.16–18 To monitor anticoagulation, activated partial thromboplastin time (HIT treatment) and activated clotting time (ACT; PCI procedures) are measured. For HIT treatment, therapeutic levels of argatroban are achieved when the activated partial thromboplastin time is 1.5–3.0 times baseline.14 For PCI, therapeutic levels of argatroban are achieved when ACT is 300–450 s.14 ,16 ,17
While guidelines for dosing and monitoring argatroban for HIT treatment and PCI procedures are well established, guidelines for use of this drug for cerebral angiography have not been determined. Our center's protocol for use of argatroban for neurointerventional procedures in patients with heparin sensitivity takes into consideration the above mentioned guidelines. Dosing used for HIT treatment provides subtherapeutic levels of argatroban while dosing for PCI provides supratherapeutic levels needed for cerebral angiography. Our protocol was designed to produce serum argatroban levels approximately in the middle of the established guidelines. Our protocol for drug administration and monitoring is outlined in table 1. Following a loading dose of 4.0 μg/kg/min infused over 10 min, an ACT measurement is obtained at 10 and 20 min after administration of the loading dose. If ACT is within the target range (200–250 s), the patient is switched to a maintenance dose of 1.0 μg/kg/min. If long term anticoagulation is necessary, patients are maintained on argatroban while oral warfarin therapy is initiated. Once an international normalized ratio (INR) of 4 is obtained, patients are removed from argatroban maintenance therapy. Because INR is falsely elevated in patients on argatroban, an INR of 4 in those patients receiving both argatroban and warfarin corresponds to an appropriate INR of 2 once argatroban is stopped.
There have been no previous reports documenting the use of argatroban during neurointerventional procedures. We report here its use in a series of three patients with established heparin sensitivity. All patients had previously undergone cerebral angiography using heparin but later developed HIT necessitating the need for other methods of anticoagulation. All three patients underwent cerebral angiography to evaluate and treat cerebral vasospasm following subarachnoid hemorrhage. Patient No 1 underwent cerebral angiography for vasodilator infusion to treat vasospasm following an anterior communicating artery aneurysm rupture. Patient No 2 underwent cerebral angiography for vasodilator infusion to treat vasospasm following internal carotid artery aneurysm rupture and superficial temporal artery to middle cerebral artery bypass. Patient No 3 underwent cerebral angiography for vasodilator infusion to treat vasospasm following clipping of an anterior communicating artery aneurysm in addition to bilateral angioplasty of both the internal carotid artery and middle cerebral artery. Two of the three patients were administered argatroban following the protocol outlined above while the third patient was on systemic argatroban due to a left vertebral artery dissection sustained during a previous angiogram. Table 2 summarizes the use of argatroban during cerebral angiography as well as patient outcomes.
Currently, the standard treatment for periprocedural anticoagulation during cerebral angiography is heparin. In patients with HIT, however, this drug choice is not acceptable, requiring alternative methods for anticoagulation in order to ensure patients do not form thrombi during angiography procedures. The most commonly used alternative is a DTI such as argatroban or bivalirudin. As discussed above, bivalirudin is a poor alternative to use during angiography because it is excreted through the kidney. Therefore, we use argatroban at our center. Argatroban is currently indicated for the management of HIT and for prophylaxis during PCI. However, there are no reports of its use during neurointerventional procedures nor are there guidelines to follow to administer this drug during such procedures. We have described our center's protocol for the administration of argatroban in the angiography suite as well as reporting on its use in three different patients. With this report, we hope to provide an alternative use for argatroban that neurointerventionalists can follow during cerebral angiography in patients with established heparin sensitivity.
Contributors MT, manuscript writing. DB, literature review. VA, manuscript editing. AA, manuscript writing, literature review, and editing.
Competing interests AA is a consultant for Cordis-Codman. VA is a consultant for eV3-Covidian and Cordis-Codman.
Ethics approval The study was approved by the institutional review board of the University of Illinois at Chicago.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.